Evaluation of Platelet Distribution Width as an Early Predictor of Acute Kidney Injury in Extensive Burn Patients

Background The extensive burns devastate trauma. The research was designed to analyse the predictive value of early platelet (PLT) indices on the development of acute kidney injury (AKI) after severe burns. Methods and Results 186 patients with extensive burns (burn area ≥30%) were eventually involved. Multivariate analyses pointed out that platelet distribution width (PDW) in the first 24 h after admission was an independent risk factor for AKI, severe AKI, and RRT requirement in patients with severe burns, and AKI risk showed an increase of 30.9% per increase of 1% in PDW (OR = 1.309, CI, 1.075–1.594, and P = 0.007). It was found that the area under the ROC curve (AUC) of PDW predicting AKI was 0.735 and that the AUC value was 0.81 for AKI after combining PDW and blood urea nitrogen (BUN). Based on the cut-off value PDW = 17.7%, patients were divided into high- (PDW ≥17.7%) and low-risk (PDW <17.7%) groups. In the KM analysis, there was a higher cumulative incidence of AKI if patients were in a high-risk group (in 30 days); and the stages of AKI showed a linear upward trend (chi-square test for linear trend P  <  0.001) as there was an increase in the risk level. Conclusion The PDW level in the early stage serves as an important risk factor for AKI, severe AKI, and RRT requirement in extensive burns. When PDW >17.7%, burn patients are not only at a higher risk for AKI but may also have higher AKI severity. Due to low cost and wide availability, PDW has the potential to be the tool that can predict AKI in extensive burn patients.


Introduction
Severe burns are devastating and are linked to a high mortality rate [1].In the world, it is found that around 11 million people can sufer burns each year, in which a total of 300,000 die [2].Acute kidney injury (AKI) generally occurs in severely burned patients and has a close linkage with short-term and long-term adverse events.In addition, it can usually cause increased patient mortality and prolonged intensive care [3].Although early kidney dysfunction may be recoverable, tissue damage is irreversible [4].Tere is a high AKI within the general incidence even though recent years have witnessed achievements in intensive care, fuid resuscitation, and renal replacement therapy (RRT) technology [5].As a result, early prediction and risk stratifcation of AKI in severe burn patients play a signifcant role in timely intervention and improved prognosis.
Platelets (PLT) are small, circulating, and anucleate cells derived from megakaryocytes in the bone marrow.Teir primary physiological role lies in sensing the damaged vessel endothelium and accumulating at the site of the vessel injury, in which place they can start blood clotting to block the circulatory leak.However, in addition to haemostasis and thrombosis, platelets are included in a lot of diverse biological processes, such as tissue repair, infammation, and antimicrobial host defense [6].
Platelet indices are investigated as biomarkers in lots of diseases, such as stroke, various cancers, and some infectious diseases [7,8].According to Osuka et al. [9], early thrombopenia is an independent risk factor for 60-day mortality within severely burned patients.Recently, Lin et al. [10] pointed out that platelet distribution width (PDW) and PDW-to-platelet ratio (PPR) were good prognostic indicators for mortality in severe burn patients.Also, Wu et al. [11] found that nadir platelet count in the frst 2 days of hemorrhagic shock serves as a new biomarker for AKI and 28-day all-cause mortality.However, it is still uncertain whether platelet indices are signifcant predictors for AKI in burn patients.
As a result, this retrospective study collected the platelet indices on admission and development of AKI in patients with severe burns.Te research aimed to validate and evaluate the predictive value of platelet indices of AKI after severe burns.Our work ofers a clinical rationale to assess patients' prognosis and enables early intervention timely.

Study Population.
Te retrospective study was carried out in the Afliated Hospital of Nantong University.It can be seen in Figure 1 that a total of 221 severe burn patients enrolled at the beginning, of which 35 were excluded, and 186 patients were fnally recruited.Te research was approved by the Medical Ethics Committee of the Hospital and was following the Helsinki Declaration.

Management and Outcome Defnitions.
Te patient care and treatment abide by the relevant guidelines (such as inhalation injury management, surgery and nutrition, fuid resuscitation, and infection prevention and treatment).On admission, fuid resuscitation was carried out on each enrolled patient in accordance with the Ruijin resuscitation formula which was generally used for China's severe burn patients [12].Te surgery was carried out in patients within 1 month of the injury (escharotomy was performed frst, and repeated autologous transplantations were followed).Airway treatment and ventilator assistance were ofered to patients with underlying airway blockage or severe hypoxemia.Patients were ofered enteral and parenteral nutrition early.Extensive burns were defned as the total body surface area (TBSA) ≥30%.Tere was an evaluation of AKI severity and incidence according to the Kidney Disease, which were the Improving Global Outcomes (KDIGO) criteria [13].Severe AKI was defned as AKI stage 2 or 3 [14].Because the baseline serum creatinine (Scr) levels before injury were often unmeasured in most patients, the frst available Scr level was the baseline Scr [5].Te urine output data heterogeneity enables the phenomenon that the assessment of AKI did not involve urine output [15,16].Te nonrenal sequential organ failure assessment (SOFA) was defned as the SOFA score with no renal component [17].Lifethreatening organ dysfunction can be represented by an increase in the SOFA score of ≥2 points [18].

Data Collection.
Each of the laboratory and clinical data was obtained from the hospital's electronic medical record (EMR) system.After admission, patients regularly underwent blood biochemical tests.Te results of the blood sample 24 h after admission were chosen to be the research variables.Te following variables were gathered, which were age, body mass index (BMI), full-thickness burns (FTBs)%, gender, inhalation injury, tracheostomy, SOFA score, burn mechanism, TBSA%, frst 24 h fuid resuscitation volume after injury, MPV (mean platelet volume), PDW, PLT, blood urea nitrogen (BUN), HGB (hemoglobin), ABSI score, the 30-day development of AKI, as well as patients required RRT and in-hospital-survival.

Statistical Analysis.
Te statistics were explored via the SPSS 23.0, MedCal 20.022, and GraphPad 9.3.1.For exploring the distribution characteristics of each variable, the Shapiro-Wilk test was used.Te continuous variables that follow the normal distribution were expressed as the mean ± standard deviation.Te t-test of the students was applied to show that there were some diferences between the two normally distributed variables.In case of no normal distribution, then the continuous variables were expressed as the median (interquartile range (IQR)) and checked through the Mann-Whitney U test.By using the chi-square or Fisher's exact test, the categorical data were reported as a percentage and also compared.Te chi-square test for trend was used to evaluate the proportionate trends.An exploration of the risk factors that afect AKI was carried out through multivariate logistic regression analysis.Te multicollinearity test included the variance infation factor (VIF) for assessing multicollinearity.For presenting and 2 Emergency Medicine International comparing the predictive values of AKI risk factors, the receiver operating characteristic (ROC) curves were used.We also simultaneously calculated the specifcity, sensitivity, and cut-of value.Te Youden index was used to decide the cut-of value.Te AUC values were compared by the Z-test.
Te Kaplan-Meier (KM) method and log-rank test were used to explore and compare the cumulative incidences of AKI in 30 days.P value <0.05 was considered statistically signifcant.  1 shows the comparison of the baseline and demographic diferences between AKI and non-AKI groups.In terms of BMI, age, gender, PLT, MPV, and burn mechanism, it is found that no obvious diference was between AKI and non-AKI groups (P > 0.05).In comparison with the non-AKI ones, it is found that AKI patients were seen to have signifcantly higher TBSA, FTBs, ABSI, nonrenal SOFA scores, the proportion of patients with the SOFA score ≥2, frst 24 h fuid amount, inhalation injury proportion, BUN, HGB, PDW, and mortality (P > 0.05).

Logistic Regression
Analysis.Among the platelet indices, only PDW is the signifcant risk variable for AKI (Table 1).Ten, the multivariate logistic regression analysis was applied to evaluate the PDW, HGB, frst 24 h fuid amount, and ABSI score for the AKI, severe AKI, and RRT requirements (ABSI primarily combines data on the age, TBSA, FTBs, gender, and inhalation injury of the burn patients and presents the basic characteristics and severity of the burn patients on admission.Terefore, the ABSI score was added to adjust the burning burden in the multivariate analysis.Hemoglobin concentration in blood was taken as a marker of hemoconcentration, which may afect the outcomes.Te multicollinearity test showed no obvious linearity between clinical outcomes and factors, all VIF <5 (Figure 2). Figure 2 showed the analysis results.After the multivariate analyses, it was found that PDW represented an independent risk factor for AKI (OR � 1.309, CI, 1.075-1.594,and P � 0.007), severe AKI (OR � 1.291, CI, 1.044-1.595,and P � 0.018), and RRT requirements (OR � 1.481, CI, 1.044-2.100,and P � 0.028).For each increase of 1% in PDW, the risk of AKI showed an increase of 30.9%.

ROC Curve Analysis.
Te ROC curves were used to evaluate the ability of PDW, BUN (some research see BUN as the related factor for AKI occurrence [19][20][21]), and the joint detection of BUN and PDW in predicting AKI.When predicting AKI (Figure 3), the AUC of PDW was 0.735, which was very close to the value of BUN (AUC � 0.785).Tere was no statistically signifcant diference (Z � 0.912 and P � 0.361).Te cut-of value of PDW was 17.7% (sensitivity: 48.8, specifcity: 89.0).Tere was a higher AUC of 0.813 in the combined test in comparison with PDW and BUN (Z � 2.150 and 1.177, P � 0.031 and � 0.239, separately).

KM Analysis.
Te cut-of value of PDW (PDW � 17.7%) was used to classify the patients into high-risk (PDW ≥17.7%) and low-risk (PDW <17.7%) groups.Te Kaplan-Meier method was used to identify the 30-day cumulative rate of AKI in diferent groups (Figure 4).Tere were signifcantly higher cumulative incidence curves of PDW ≥17.7% compared to those of PDW <17.7%.Accordingly, there was a higher cumulative incidence of AKI if PDW ≥17.7. 5 compared percentages of the high-risk and low-risk groups in diferent AKI stages.Te proportion of the low-risk group (89.0%) in patients without AKI is much higher than that of the highrisk group (11.0%).At the same time, the proportion of the low-risk group (30.0%) in stage 3 AKI patients is signifcantly lower than that of the high-risk group (70.0%), with all P < 0.05.On the whole, AKI staging presented a linear upward trend as there was an increase in the risk level (the chi-square test for linear trend P < 0.001).

Discussion
Recently, platelet indices have been proposed as the predictors of thrombotic and infammatory conditions, which were mainly in patients with thrombotic and infammatory conditions, and were considered as risk factors for reduced survival in patients with diferent kinds of malignancies, including non-small cell lung cancer, cervical cancer, pancreatic adenocarcinoma, and colon cancer [7,8,22].Also, their relationship with extensive burns was investigated.

Emergency Medicine International
According to Cato et al. [23], platelet count and rBaux score together generate moderate discriminatory power for survival at less than 24 h after injury.Huang et al. [24] reported that blunted daily increase in PCs (platelet counts) is linked to an increase in 30-day mortality.Similarly, Lin et al. [10] found that early postburn PDW was an independent risk factor for 120-day mortality in severe burn patients.In these studies, an association between platelet indices and burn mortality was revealed and prognostic information for the mortality risk assessment in severely burned patients was provided.However, burn patients mainly died of multiple organ failure, and there is no report concerning a prognostic association between platelets and AKI in burn patients.
In this study, it is shown that the early PDW level may be a valuable predictor for AKI after severe burns.Te major fndings are as follows: (1) early PDW after admission was an independent risk factor for AKI, severe AKI, and RRT requirement in extensive burns even after multivariate logistic regression analyses with HGB, frst 24 h fuid amount, and ABSI score.Te risk showed an increase of 30.9% for AKI occurrence given per increase of 1% in PDW; (2) the AUC value of PDW was 0.735 in predicting AKI.Tis result was not statistically signifcant compared with 0.78 of BUN.Teir combined application had a higher AUC value (0.81) upon predicting AKI; (3) the KM analysis showed that AKI had higher cumulative incidence if PDW ≥17.7%; and (4) the severity of AKI presented a linear upward trend when the risk level increases (chi-square test for trend P < 0.001).In the abovementioned results, the potential predictive power and the specifc predictive values of the early postburn PDW level for AKI were shown.Using the cut-of value (PDW � 17.7%), it is better to be able to distinguish patients at diferent risks.
AKI in the early stage of extensive burns can be brought by denatured proteins, cardiac insufciency, hypovolemia, and infammatory factors produced by tissue destruction and nephrotoxicity caused by drugs [25][26][27].Severe sepsis is often seen as a signifcant reason for the occurrence of advanced AKI [28,29].For a long time, hypovolemia and inadequate fuid resuscitation were seen to be the main factors of early AKI.However, the previous study showed that AKI is likely to still occur after enough fuid resuscitation [30].Besides, the research on critical care patients shows positive fuid intake is likely to negatively afect renal function and mortality [31][32][33].In the results, the shock degree brought by the initial burn damage and the following generation of mass infammatory factors is likely to be a major reason for AKI in burns.Terefore, the indicators which refect the conditions of tissue perfusion and original burn severity may be adequate predictors of AKI [34].In this study, it was found that AKI patients had been given signifcantly more fuid volume in 24 hours than non-AKI patients (Table 1).Te higher and abnormal hemoglobin values in AKI patients suggest that there may be a greater degree of blood concentration and fuid loss after injury, which may infuence the development of AKI in Note.Data are presented as the mean ± SD, median (interquartile range), or number (%).BMI, body mass index; AKI, acute kidney injury; TBSA, total burn surface area; FTBs, full-thickness burns; ABSI, abbreviated burn severity index; SOFA, sequential organ failure assessment score; PLT, platelet; MPV, mean platelet volume; PDW, platelet distribution width; BUN, blood urea nitrogen; HGB, hemoglobin.Emergency Medicine International patients.However, after multiple regression analysis that involves these variables, it was found that PDW was still an independent risk factor for AKI (Figure 2).Platelets behave as a major role in coagulation and infammation and are also involved in acquired and innate immune responses.According to Van Linden et al. [35], thrombocytopenia was a signifcant risk factor for postoperative AKI after the aortic valve implantation.As pointed out by Kertai et al. [36], the platelet nadir after the coronary artery bypass grafting had a signifcant association with postoperative AKI.However, this situation may be more special in patients with severe burns.Te platelets are consumed in the burn wound, and due to this, dermal vasculature and subsequent microthrombi formation are 0.0 0.5 1.0 1. 5   Emergency Medicine International destructed.Te microthrombi form in 24−48 h.Te permeability of surrounding vessels shows an increase and is likely to cause increased activation of platelets via interacting with the tissue factors on the subendothelium and activated clotting factors [37,38].Te activation of platelets brings pseudopodia formation and some other morphological changes.In the platelet activation, some morphological alterations can be caused; that is, it seems that activated platelets are larger by becoming spherical and forming pseudopodia.Accordingly, platelets with enhanced pseudopodia number and size will be diferent in size that brings about alterations in PDW [39].In another research [40], a high PDW value showed a broad range of PLT volume, which was brought about by destruction, swelling, and   Emergency Medicine International immaturity.Tis means that a higher PDW value enables more obvious PLT damage and immaturity.Terefore, early PDW can not only refect the severity of burns but also the formation of microthrombi in the microcirculation, thus refecting the perfusion status of tissues and becoming an AKI predictor.However, there are some limitations in this study.First all, in this single-center retrospective study, a preliminary exploration of the relationship between platelet parameters and AKI in extensive burn patients was carried out.However, there is a limited number of AKI (41/186) and severe AKI (27/186), especially for RRT-requiring patients (8/186).Te relatively small number of patients may result in statistical instability.Tus, multicenter prospective research with sample size expansion and further validation should be made.Secondly, Scr is mainly applied to decide the AKI stage and presence.We designated the frst available Scr as the baseline Scr since most patients had no baseline Scr measured before injury [41].Tis is likely to infuence results.At last, our research group did not involve children since they are not yet physically developed, and therefore, further research can be carried out within the underage population.

Conclusion
In the research, early PDW after admission represented an independent risk factor for AKI, severe AKI, and RRT requirement in extensive burns, and the risk of AKI showed an increase by 30.9% per increase of 1% in PDW.Compared to a single variable applied for prediction, there was a higher predictive value for AKI development within PDW combined with BUN.If PDW >17.7%, burn patients are at a higher risk for AKI and are likely to have higher AKI severity.Trough low cost and wide availability, it can be seen that PDW has the potential to be the tool that can predict AKI in extensive burn patients.Emergency Medicine International

Figure 1 :
Figure 1: Flowchart of participants presenting the application of inclusion and exclusion criteria.BMI: body mass index; FTBs: fullthickness burns.

Figure 3 :
Figure 3: Receiver operator characteristic curves of PDW and BUN and the joint detection factor of PDW and BUN for the prediction of AKI.

Figure 4 :
Figure 4: KM curve analysis of AKI development within 30 days based on PDW ≥17.7% and PDW <17.7% in severe burn patients.

Figure 5 :
Figure5: Te percentages of high-risk and low-risk groups in diferent AKI stages.AKI staging presented a linear upward trend as there was an increase of the risk level (the chi-square test for trend P < 0.001).